Discovery of a novel, liver-targeted thyroid hormone receptor-β agonist, CS271011, in the treatment of lipid metabolism disorders

Lin, Suwen; Huang, Shengjian; Deng, Zhou; Hua, Lin; Wu, Yanyi; Lv, Shuyan; Wang, Zhiyi; Huang, Ning; Wang, Lan; Chen, Ziqi; Guo, Yu; Wang, Yin; Zhou, You; Fang, Zhengyu

doi:10.3389/fendo.2023.1109615

Cited by 4 publications

(2 citation statements)

References 25 publications

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“…Most murine models with HFD even after long-term feeding feature as steatohepatitis, but rarely liver fibrosis. Chemical reagents such as CCL4 can induce liver injury and fibrosis in different murine models [ 26 ]. Furthermore, animals that received WD and CCL4 simultaneously are similar to the corresponding human disease.…”

Section: Resultsmentioning

confidence: 99%

“…Several THR-β agonists with oral bioavailability and liver-targeted properties have been developed and showed preclinical efcacy in NAFLD and nonalcoholic steatohepatitis (NASH) models [21][22][23][24][25][26]. Recently, two THR-β agonists, MGL3196 (Resmetirom) and VK2809, have progressed to phase III clinical trials for the treatment of NASH and hyperlipidemia [19,27].…”

Section: Introductionmentioning

confidence: 99%

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CS27109, A Selective Thyroid Hormone Receptor-β Agonist Alleviates Metabolic-Associated Fatty Liver Disease in Murine Models

Huang¹,

Deng²,

Wang³

et al. 2023

International Journal of Endocrinology

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Background/Aim. Thyroid hormone receptor-β (THR-β) agonists play crucial roles in dyslipidemia and metabolic associated fatty liver disease (MAFLD). We developed a novel oral and liver-targeted THR-β agonist, CS27109, and evaluated its efficacy in the treatment of metabolic disorders. Materials and Methods. We evaluated in vitro and in vivo efficacy and/or safety of CS27109 along with MGL3196 (a phase III THR-β agonist). Results. CS27109 showed pronounced activity and selectivity to THR-β and favorable PK properties, which was equivalent to MGL3196. In the hamster model, animals treated with a high dose of CS27109 showed equivalent reductions in serum TC and LDL-c with groups treated with MGL3196. In the rat model, CS27109 and MGL3196 reduced serum ALT, TC, TG, LDL-c, liver weight ratio, and liver steatosis. CS27109 simultaneously decreased liver TG and TC, and MGL3196 additionally reduced AST. In the mouse model, CS27109 dose-dependently reduced serum AST, ALT, liver inflammation, and NAS score, and also downregulated TC, LDL-c, liver steatosis, and fibrosis, but not in a dose-dependent manner. MGL3196 revealed an equivalent effect with CS27109 in that model. CS27109 also exhibited tolerable toxicity to the heart. Conclusions. CS27109 shows comparative in vitro and in vivo efficacy with MGL3196, suggesting its potential therapeutic application in the treatment of MAFLD such as dyslipidemia and steatohepatitis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CS27109, A Selective Thyroid Hormone Receptor-β Agonist Alleviates Metabolic-Associated Fatty Liver Disease in Murine Models

Huang¹,

Deng²,

Wang³

et al. 2023

International Journal of Endocrinology

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Biochemical basis and therapeutic potential of mitochondrial uncoupling in cardiometabolic syndrome

dos Santos,

Brisnovali,

Goedeke

2024

Biochemical Journal

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Mild uncoupling of oxidative phosphorylation is an intrinsic property of all mitochondria, allowing for adjustments in cellular energy metabolism to maintain metabolic homeostasis. Small molecule uncouplers have been extensively studied for their potential to increase metabolic rate, and recent research has focused on developing safe and effective mitochondrial uncoupling agents for the treatment of obesity and cardiometabolic syndrome (CMS). Here, we provide a brief overview of CMS and cover the recent mechanisms by which chemical uncouplers regulate CMS-associated risk-factors and comorbidities, including dyslipidemia, insulin resistance, steatotic liver disease, type 2 diabetes, and atherosclerosis. Additionally, we review the current landscape of uncoupling agents, focusing on repurposed FDA-approved drugs and compounds in advanced preclinical or early-stage clinical development. Lastly, we discuss recent molecular insights by which chemical uncouplers enhance cellular energy expenditure, highlighting their potential as a new addition to the current CMS drug landscape, and outline several limitations that need to be addressed before these agents can successfully be introduced into clinical practice.

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Beneficial effects of MGL‐3196 and BAM15 combination in a mouse model of fatty liver disease

Zhou,

Li,

Byrne

et al. 2024

Acta Physiologica

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Background and AimMetabolic dysfunction‐associated steatohepatitis (MASH) is a metabolic disorder with limited treatment options. The thyroid hormone receptor (THR)‐β agonist resmetirom/MGL‐3196 (MGL) increases liver fat oxidation and has been approved for treating adult MASH. However, over 60% of patients receiving MGL treatment do not achieve MASH resolution. Therefore, we investigated the potential for combination therapy of MGL with the mitochondrial uncoupler BAM15 to improve fatty liver disease outcomes in the GAN mouse model of MASH.MethodsC57BL/6J male mice were fed GAN diet for 38 weeks before stratification and randomization to treatments including MGL, BAM15, MGL + BAM15, or no drug control for 8 weeks. Treatments were admixed in diet and mice were pair‐fed to control for drug intake. Treatment effectiveness was assessed by body weight, body composition, energy expenditure, glucose tolerance, tissue lipid content, and histological analyses.ResultsMGL + BAM15 treatment resulted in better efficacy versus GAN control mice than either monotherapy in the context of energy expenditure, liver fat loss, glucose control, and fatty liver disease activity score. Improvements in ALT, liver mass, and plasma cholesterol were primarily driven by MGL, while improvements in body fat were primarily driven by BAM15. No treatments altered liver fibrosis.ConclusionsMGL + BAM15 treatment had overall better efficacy to improve metabolic outcomes in mice fed GAN diet than either monotherapy alone. These data warrant further investigation into combination therapies of THR‐β agonists and mitochondrial uncouplers for the potential treatment of disorders related to fatty liver, obesity, and insulin resistance.

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Discovery of a novel, liver-targeted thyroid hormone receptor-β agonist, CS271011, in the treatment of lipid metabolism disorders

Cited by 4 publications

References 25 publications

CS27109, A Selective Thyroid Hormone Receptor-β Agonist Alleviates Metabolic-Associated Fatty Liver Disease in Murine Models

CS27109, A Selective Thyroid Hormone Receptor-β Agonist Alleviates Metabolic-Associated Fatty Liver Disease in Murine Models

Biochemical basis and therapeutic potential of mitochondrial uncoupling in cardiometabolic syndrome

Beneficial effects of MGL‐3196 and BAM15 combination in a mouse model of fatty liver disease

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